Smooth muscle cells (SMC) accumulate in developing lesions of atherosclerosis in response to inflammatory products, including platelet- derived growth factor (PDGF). SMC in vivo are normally surrounded by extracellular matrix (ECM), including type 1 collagen, while in atherogenesis, the ECM is degraded and new ECM components are synthesized and assembled. We have demonstrated that culture of human SMC on fibrillar collagen mimics the phenotypic state of SMC in vivo of the normal media, and in vitro fibrillar collagen arrests SMC in the G1 phase of the cell cycle, independent of the presence of PDGF, while monomer collagen supports SMC proliferation. We have further demonstrated that non-permissive and permissive environments for SMC proliferation appear to target a common pathway-matrix-integrin regulation of the cdk2 inhibitor, p27/Kip1. Separate studies have established that degraded collagen transduced distinct signals that lead to dissolution of focal adhesions, including rapid cleavage of focal adhesion kinase and paxillin. Thus, integrin-mediated signals from various forms of type I collagen lead to specific and rapid modulation of the integrin signaling complex and the responsiveness of SMC to PDGF. This has led to the hypothesis that the extracellular matrix within the normal media may be non-permissive for SMC migration and proliferation, and that degraded matrix may release SMC from this non-permissive state. The proposed studies will test this hypothesis and the role of PDGF in vivo with the following specific aims: I. evaluate the signaling pathways responsible for modulating levels of the cdk inhibitor p27/Kip1 under permissive and non-permissive conditions for SMC; 2. examine the molecular pathways responsible for degraded type I collagen dissolution of the focal adhesion complex; and 3. test the role of PDGF in the formation of lesions of atherosclerosis by evaluation chimeras in which circulating cells (major sources of PDGF in developing lesions are macrophages and platelets) of Apo E-/- mice are replaced with fetal liver cells from PDGF-/- embryos.